Method for preparation of sulphostin and its analogue or intermediates thereof

ABSTRACT

A method for preparing a compound represented by the following general formula (5)  
                 
 
where, n is an integer of 0 to 3; and Y represents a protecting group for an amino group, the method including the steps of reacting a compound represented by the following general formula (3)  
                 
         where n and Y are as described above, with a silylating agent, and subsequently reacting it with P (═O) T 3 , where T represents a halogen atom, and further with ammonia. 
 
A method for preparing an optically active intermediate of sulphostin or an analogue thereof, which is an optically active amine salt of an optically active compound represented by the following general formula (8)  
                 
 
where n is an integer of 0 to 3; Y represents a protecting group for the amino group; and each configuration at C* and P* may be the same or different and indicates S or R, the method including reacting a compound represented by the following general formula (7)  
                 
where n and Y are as described above; and the configuration of C* indicates either of S or R, with an optically active amine, and resolving the formed diastereomeric salt by fractional crystallization.

TECHNICAL FIELD

The present invention relates to a new method for preparing sulphostin,a physiologically active substance, an analogue thereof and apreparation intermediate thereof.

BACKGROUND ART

Sulphostin and analogues of sulphostin represented by the followinggeneral formula (1) (where n is an integer of 0 to 3) are new organiccompounds having a dipeptidyl peptidase IV inhibitory action. Inparticular, a compound represented by the following general formula (2)having the structure in which, in the general formula (1), n is 2, theconfiguration at C* is S, the configuration at P* is R, is described assulphostin in the following literature.

These compounds are expected to be applied to medicines, such as animmunomodulator, a hormone regulator, an anti-HIV drug, an antiallergicdrug, an antiinflammatory drug and an antirheumatic drug (WO99/25719).

In addition, as for preparation of the above compound, because afermentation method has low productivity and is not suitable for massproduction for the present, a preparation method by synthesis isreported (JP-A-2000-327689). The preparation method employs a process ofactivating an amide with the use of a super strong base under ultra lowtemperature (−78° C.) conditions, and then reacting phosphonyl chlorideand liquid ammonia under similar temperature conditions, in the step ofpreparing phosphoric acid amide. In the step of resolution,chromatography is used, so that the resolution is imperfect thus makingit difficult to provide a product of high purity. Accordingly, the abovepreparation method cannot produce a large amount of the above compoundin an industrial scale.

DISCLOSURE OF THE INVENTION

The present invention provides a new method for preparing a preparationintermediate of sulphostin and an analogue of sulphostin by a mild andeasy operation, which aims at mass production which has been difficultaccording to the prior art.

In addition, the present invention provides a new method for preparingan optically active intermediate, which aims at mass production ofsulphostin and analogues thereof having a high optical purity, which hasbeen conventionally difficult.

The present inventors has made an extensive investigate, and found amethod for preparing the compounds represented by the following generalformula (5) at a high yield under more moderate and milder conditionsthan those in the prior art, by silylating a compound represented by thegeneral formula (3) in a mild condition at first, and then reacting itwith a phosphorus oxyhalide represented by the general formula (4) andammonia. Secondly, the present inventors found a method of sulfonatingthe compound represented by the general formula (5′), then reacting theresulting compound represented by the general formula (7) with anoptically active amine and fractionating the resulting diastereomer saltby fractional crystallization, to obtain an optically active amine saltof an optically active substance represented by the general formula (8).The present inventors then obtained sulphostin and the analogues thereofrepresented by the general formula (1) by subsequently removing aprotecting group for an amino group and an optically active amine by aconventional process. Thus, the inventors found a new selection methodfor obtaining sulphostin and the analogues thereof represented by thegeneral formula (1) from compounds represented by the general formula(3), and completed the present invention.

More specifically, the present invention relates to the following (i) to(xxv).

-   (i) A method for preparing a compound represented by the following    general formula (5)-    where n is an integer of 0 to 3; and Y represents a protecting    group for an amino group, comprising the steps of reacting a    compound represented by the following general formula (3)-    where n and Y are as described above, with a silylating agent, and    subsequently reacting it with a phosphorus oxyhalide represented by    the general formula (4)    P(═O)T₃  (4)-    where T is a halogen atom and further with ammonia.-   (ii) The preparation method according to the above (i), wherein the    above described Y is a protecting group of a carbamate type or an    amide type.-   (iii) The preparation method according to the above (ii), wherein    the above described Y is a benzyloxycarbonyl group or a    tert-butoxycarbonyl group optionally substituted; and n is 2.-   (iv) The preparation method according to any one of the above (i) to    (iii), wherein the compound represented by the above described    general formula (3) is an optically active substance.-   (v) The preparation method according to any one of the above (i) to    (iv), wherein T is a chlorine atom in the above described general    formula (4).-   (vi) The preparation method according to any one of the above (i) to    (v), wherein the above described silylating agent is represented by    the following general formula (6)-    where R1, R2 and R3 each independently represent a lower alkyl    group or an aryl group; and X represents a halogen atom or a    fluorinated alkyl sulfonate.-   (vii) The preparation method according to the above (vi), wherein    the above described silylating agent is trimethylsilyl chloride.-   (viii) The preparation method according to any one of the above (i)    to (vii), wherein a reaction temperature is −20 to 80° C. in the    steps of preparing a compound represented by the general formula (5)    from a compound represented by the above described general formula    (3).-   (ix) A method for preparing an optically active intermediate of    optically active sulphostin or analogues thereof, which is an    optically active amine salt of an optically active compound    represented by the following general formula (8)-    where n is an integer of 0 to 3; Y represents a protecting group    for the amino group; and each configuration at C* and P* may be the    same or different and indicates S or R, comprising the steps of    reacting a compound represented by the following general formula (7)-    where n and Y are as described above; and the configuration of C*    indicates either S or R, with an optically active amine, and    resolving a formed diastereomeric salt by fractional    crystallization.-   (x) A method for preparing an optically active sulphostin or    analogues thereof represented by the following general formula (1)-    where n is an integer of 0 to 3; and each configuration of C* and    P* may be the same or different and indicates S or R, comprising the    steps of reacting a compound represented by the following general    formula (7)-    where n is an integer of 0 to 3, Y represents a protecting group    for an amino group, and a configuration of C* indicates either of S    or R, with an optically active amine, resolving a formed    diastereomeric salt by fractional crystallization to obtain an    optically active amine salt of an optically active compound    represented by the following general formula (8)-    (where n is an integer of 0 to 3, Y represents the protecting group    of the amino group; n, C* and P* are the same meanings as above),    and then removing the protecting group for the amino group and the    optically active amine by a conventional process.-   (xi) The method according to the above (ix) or (x), wherein the    optically active amine is represented by the following general    formula (9)-    where Ar represents a phenyl group which may have a substituent    group; R1′ represents a lower alkyl group which may have a    substituent group or an aryl group which may have a substituent    group; each of R2′ and R3′ may be the same or different and    represents a hydrogen atom or a lower alkyl group; each    configuration of C*1 and C*2 may be the same or different and    indicates S or R.-   (xii) The method according to the above (ix) or (x), wherein the    above described optically active amine is a compound selected from    the group consisting of (1R,2S)-(−)-2-amino-1,2-diphenylethanol,    (1S,2R)-(+)-2-amino-1,2-diphenylethanol, (1R,2S)-(−)-ephedrine,    (1S,2R)-(+)-ephedrine, (1R,2S)-(−)-N-methylephedrine,    (1S,2R)-(+)-N-methylephedrine, (1R,2S)-(−)-4-hydroxyephedrine,    (1S,2R)-(+)-4-hydroxyephedrine, (1R,2S)-(−)-norephedrine,    (1S,2R)-(+)-norephedrine, (1R,2S)-(−)-3,4-dihydroxynorephedrine,    (1S,2R)-(+)-3,4-dihydroxynorephedrine,    (1S,2R)-(−)-2-dibutylamino-1-phenyl-1-propanol,    (1R,2S)-(+)-2-dibutylamino-1-phenyl-1-propanol,    (1S,2S)-(+)-pseudoephedrine, (1R,2R)-(−)-pseudoephedrine,    (1S,2S)-(+)-N-methylpseudoephedrine,    (1R,2R)-(−)-N-methylpseudoephedrine,    (1S,2S)-(+)-2-amino-3-methoxy-1-phenyl-1-propanol,    (1R,2R)-(−)-2-amino-3-methoxy-1-phenyl-1-propanol,    erythro-1,2-diphenyl-2-(propylamino)ethanol,    erythro-2-(isopropylamino)-1,2-diphenylethanol,    (1R,2R)-(−)-2-amino-1-phenyl-1,3-propanediol,    (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol,    (1R,2R)-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol and    (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.-   (xiii) The method according to the above (ix) or (x), wherein the    above described optically active amine is a compound selected from    the group consisting of (1R,2S)-(−)-2-amino-1,2-diphenylethanol,    (1S,2R)-(+)-2-amino-1,2-diphenylethanol, (1R,2S)-(−)-ephedrine,    (1S,2R)-(+)-ephedrine, (1R,2S)-(−)-N-methylephedrine,    (1S,2R)-(+)-N-methylephedrine, (1R,2S)-(−)-4-hydroxyephedrine,    (1S,2R)-(+)-4-hydroxyephedrine, (1R,2S)-(−)-norephedrine,    (1S,2R)-(+)-norephedrine, (1R,2S)-(−)-3,4-dihydroxynorephedrine,    (1S,2R)-(+)-3, 4-dihydroxynorephedrine,    (1S,2R)-(−)-2-dibutylamino-1-phenyl-1-propanol and    (1R,2S)-(+)-2-dibutylamino-1-phenyl-1-propanol.-   (xiv) The method according to the above (ix) or (x), wherein the    above described optically active amine is    (1R,2S)-(−)-2-amino-1,2-diphenylethanol or    (1S,2R)-(+)-2-amino-1,2-diphenylethanol.-   (xv) The method according to any one of the above (ix) to (xiv),    wherein Y in the above general formula (7) is a protecting group of    a carbamate type or an amide type.-   (xvi) The method according to any one of the above (ix) to (xiv),    wherein Y in the above described general formula (7) is a    benzyloxycarbonyl group or a tert-butoxycarbonyl group that may have    a substituent group; and n is 2.-   (xvii) The method according to any one of the above (ix) to (xiv),    wherein Y in the general formula (7) is an unsubstituted    benzyloxycarbonyl group; and n is 2.-   (xviii) The method according to any one of the above (ix) to (xvii),    wherein the compound having the configuration of S at C* and the    configuration of S at P* in the above described general formula (8)    is obtained by reacting 1 mol of a compound having the configuration    of S at C* in the above general formula (7), with 0.2 to 1.4 mol    equivalent of the optically active amine having the configuration of    S at C*1 and the configuration of R at C*2 in the above described    general formula (9), as a hardly soluble salt consisting of 1 part    of itself and 1 part of the above optically active amine.-   (xix) The method according to any one of the above (ix) to (xvii),    wherein the compound having the configuration of S at C* and the    configuration of R at P* in the above described general formula (8)    is obtained by reacting 1 mol of a compound having the configuration    of S at C* in the above described general formula (7), with 1.5 to    10.0 mol equivalent of an optically active amine having the    configuration of S at C*1 and the configuration of R at C*2 in the    above described general formula (9), as a hardly soluble salt    consisting of 1 part of itself and 2 part of the above optically    active amine.-   (xx) The method according to any one of the above (ix) to (xvii),    wherein the compound having the configuration of R at C* and the    configuration of R at P* in the above described general formula (8)    is obtained by reacting 1 mol of a compound having the configuration    of R at C* in the above described general formula (7), with 0.2 to    1.4 mol equivalent of an optically active amine having the    configuration of R at C*1 and the configuration of S at C*2 in the    above described general formula (9), as a hardly soluble salt    consisting of 1 part of itself and 1 part of the above optically    active amine.-   (xxi) The method according to any one of the above (ix) to (xvii),    wherein the compound having the configuration of R at C* and the    configuration of S at P* in the above described general formula (8)    is obtained by reacting 1 mol of a compound having the configuration    of R at C* in the above described general formula (7), with 1.5 to    10.0 mol equivalent of an optically active amine having the    configuration of R at C*1 and the configuration of S at C*2 in the    above described general formula (9), as a hardly soluble salt    consisting of 1 part of itself and 2 part of the above optically    active amine.-   (xxii) The method according to the above (ix), wherein the optically    active amine salt of an optically active substance represented by    the following general formula (8)-    where n is an integer of 0 to 3; Y represents a protecting group    for the amino group; and each configuration at C* and P* may be the    same or different and indicates S or R, is obtained by sulfonating a    compound represented by the following general formula (5′)-    where n and Y are as described above; and the configuration at C*    indicates S or R, by sulfur trioxide, reacting the resulting    compound represented by the general formula (7) with an optically    active amine without isolating it, and resolving a formed    diastereomeric salt with a fractional crystalliation process.-   (xxiii) The preparation method according to any one of (i),    (ix), (x) and (xxii), wherein the optically active sulphostin or the    analogue thereof represented by the following general formula (1)-    where n is an integer of 0 to 3; each configuration at C* and P*    may be the same or different and indicates S or R, is obtained by    reacting a compound represented by the following general formula    (3′)-    where n is an integer of 0 to 3, Y represents a protecting group    for the amino group, and the configuration at C* indicates S or R,    sequentially with a sililating agent, with a phosphorus oxyhalide    represented by the general formula (4)    P(═O)T₃  (4)-    where T represents a halogen atom, and further with ammonia;    sulfonating the resulting compound represented by the following    general formula (5′)-    where n, Y and C* are as described above, with sulfur trioxide;    reacting the resulting compound represented by the general    formula (7) with an optically active amine, without isolating it;    resolving a formed diastereomeric salt with a fractional    crystallization process to obtain an optically active amine salt of    an optically active substance represented by the following general    formula (8)-    where n and Y are as described above; and C* and P* have the same    meanings as above); and then removing the protecting group of the    amino group and the optically active amine with a conventional    process.-   (xxiv) A salt of an optically active compound represented by the    following general formula (8)-    where n is an integer of 0 to 3; Y represents a protecting group    for the amino group; and each configuration at C* and P* may be the    same or different and indicates S or R, with an optically active    amine represented by the following general formula (9)-    where Ar represents a phenyl group which may have a substituent    group; R1′ represents a lower alkyl group which may have a    substituent group, or an aryl group which may have a substituent    group; each of R2′ and R3′ may be the same or different and    represents a hydrogen atom or a lower alkyl group; and each    configuration at C*1 and C*2 may be the same or different and    indicates S or R.-   (xxv) The salt according to the above (xxiv), wherein the above    described optically active amine is    (1R,2S)-(−)-2-amino-1,2-diphenylethanol or    (1S,2R)-(+)-2-amino-1,2-diphenylethanol.

BEST MODE FOR CARRYING OUT THE INVENTION

The preparation method of the present invention is described below.

In the present invention, a lower alkyl group means a saturatedhydrocarbon group having a straight chain or a branched chain having 1to 10 carbon atoms; includes, for instance, a methyl group, an ethylgroup, an n-propyl group, an n-butyl group, an n-pentyl group, ann-hexyl group, an isopropyl group, a sec-butyl group and a tert-butylgroup; and preferably includes an alkyl group having 1 to 5 carbonatoms.

In the present invention, an aryl group means an aromatic hydrocarbongroup having 6 to 10 carbon atoms, and includes, for instance, a phenylgroup and a naphthyl group.

In the phenyl group which may have a substituent group, the aryl groupwhich may have a substituent group and a benzyloxycarbonyl group whichmay have a substituent group, the number of substituent groups may be,for instance, 1 to 5, and each of several substituent groups may be thesame or different. The substituent groups include a substituent groupselected from the group consisting of an alkyl group having 1 to 5carbon atoms, an alkenyl group having 2 to 5 carbon atoms, a cycloalkylgroup having 3 to 6 carbon atoms, an alkoxyl group having 1 to 5 carbonatoms, an acyl group having 1 to 5 carbon atoms, an acyloxy group having1 to 5 carbon atoms, an acylamino group having 1 to 5 carbon atoms, ahalogenoalkyl group having 1 to 3 carbon atoms, a hydroxyl group, acyano group, a nitro group and a halogen atom.

The substituent group in the lower alkyl group which may have asubstituent group includes the above-mentioned groups in the phenylgroup which may have the substituent groups, in the aryl group which mayhave the substituent group, and in the benzyloxycarbonyl group which mayhave the substituent group.

Compounds represented by the general formula (3), which are rawmaterials in the preparation method of the present invention, can beprepared by the method according to JP-A-2000-327689.

The protecting group Y in the compound represented by the generalformula (3) may be any protecting group for the amino group used in anormal organic synthesis or the like, and includes, for instance, but isnot particularly limited to, a protecting group of a carbamate type suchas a benzyloxycarbonyl group which may have a substituent group (whenhaving the substituent groups in the benzene ring, there may be, forinstance, one to five substituent groups being as described above), anda tert-butoxycarbonyl group; and a protecting group of an amide typesuch as a formyl group, an acetyl group and a trifluoroacetyl group. Theprotecting group preferably includes a protecting group of the carbamatetype or the amide type, more preferably a benzyloxycarbonyl group whichmay have the substituent group or a tert-butoxycarbonyl group, and mostpreferably an unsubstituted benzyloxycarbonyl group.

In the general formula (3), n is an integer of 0 to 3 and preferably 2.

Specific compounds represented by the general formula (3) according tothe present invention includes:

(S)-3-benzyloxycarbonylamino-2-piperidone,

(R)-3-benzyloxycarbonylamino-2-piperidone,

(S)-3-tert-butyloxycarbonylamino-2-piperidone,

(R)-3-tert-butyloxycarbonylamino-2-piperidone,

(S)-3-benzoylamino-2-piperidone,

(R)-3-benzoylamino-2-piperidone,

(S)-3-acetylamino-2-piperidone,

(R)-3-acetylamino-2-piperidone,

(S)-3-benzyloxycarbonylamino-2-pyrrolidone,

(R)-3-benzyloxycarbonylamino-2-pyrrolidone,

(S)-3-benzyloxycarbonylamino-2-azetidinone,

(R)-3-benzyloxycarbonylamino-2-azetidinone,

(S)-3-benzyloxycarbonylamino-2-perhydroazepinone, and

(R)-3-benzyloxycarbonylamino-2-perhydroazepinone.

Reactions in the preparation method of the present invention isdescribed below.

The silylating agent for reacting with a compound of the general formula(3) includes, for instance, compounds represented by the general formula(6). In the general formula (6), lower alkyl groups represented by R1,R2 and R3 are as described above. Aryl groups represented by R1, R2 andR3 are as described above. All of R1, R2 and R3 are each preferably amethyl group. Halogen atoms represented by X in the general formula (6)include a chlorine atom, a bromine atom or an iodine atom. Fluorinatedalkylsulfonates represented by X include trifluoromethanesulfonate andpentafluoroethanesulfonate. X is preferably a chlorine atom.

The sililating agents may be used in an amount within a range of about0.5 to 20 equivalent and preferably about 1 to 5 equivalent, for acompound of the general formula (3). In the reaction of the compoundwith the silylating agent, it is considered that hydrogen of a lactam ofthe general formula (3) is substituted by the silyl group.

The specific sililating agents represented by the general formula (6)according to the present invention include:

trimethylsilyl chloride,

trimethylsilyl bromide,

trimethylsilyl iodide,

trimethylsilyl trifluoromethanesulfonate,

trimethylsilyl pentafluoroethanesulfonate,

dimethylethylsilyl chloride and

dimethylisopropylsilyl chloride.

A solvent for the reaction may be any solvent for making the reactionproceed, and includes, but is not particularly limited to, aromatichydrocarbons such as benzene, toluene and xylene; ethers such astetrahydrofuran, dioxane, isopropylether, 2-methoxyethylether anddiethylether; hydrocarbons such as hexane, heptane and octane;halogenated hydrocarbons such as chloroform, dichloromethane and1,2-dichloroethane; esters such as methyl acetate, ethyl acetate andbutyl acetate; nitrites such as acetonitrile and propionitrile; andmixed solvents consisting of an appropriate combination of these organicsolvents. The solvent is preferably an aromatic hydrocarbon such astoluene or a halogenated hydrocarbon such as dichloromethane, and morepreferably toluene. The reaction temperature is in a range of −50° C. toa temperature at which the used solvent is refluxed, and is preferably−5° C. to 60° C. The reaction time is not particularly limited to, butis any of time in which the reaction is finished, and is preferably in arange of one minute to 72 hours.

A base may be used in the above reaction as needed. For instance, anorganic base such as triethylamine and diisopropylethylamine and aninorganic base such as sodium bicarbonate can be used, but preferably anorganic base such as triethylamine and diisopropylethylamine is used.The bases may be used in an amount within a range of 0.5 to 20equivalent and preferably of 1 to 5 equivalent, for a compoundrepresented by the general formula (3).

The reagent which is used for introducing a phosphoric acid derivativeinto a lactam ring includes phosphorus oxyhalide represented by P(═O)T₃of the general formula (4). T in P(═O)T₃ represents a halogen atom suchas a fluorine atom, a chlorine atom and a bromine atom, and preferablyis a chlorine atom. Specific examples of P(═O)T₃ represented by thegeneral formula (4) include:

phosphorus oxychloride and

phosphorus oxybromide.

Direct addition of the reagent into a reaction solution having finishedthe silylization, forms a bond between a nitrogen atom on the ring ofthe compound (3) and a phosphorus atom. The ratio of P(═O)T₃to thecompound of the general formula (3) may be in a range of 1 to 20equivalent, and preferably 3 to 5 equivalent. The reaction time is notlimited to, but and may be any time in which the reaction is finished,and preferably is in a range of 12 to 120 hours. The reactiontemperature is in a range of −50° C. to the temperature at which a usingsolvent is refluxed.

Subsequent addition of ammonia to the reaction solution can lead topreparation of a compound of the general formula (5), which is aphosphoric amide. Methods for adding ammonia includes a method fordirectly feeding a gaseous ammonia to a reaction vessel, a method foradding a liquid ammonia, an ammonia-containing solution such as anaqueous solution, a methanol solution and an ethanol solution ofammonia. A preferable adding method is adding the reaction solutiondropwise to an aqueous solution of ammonia. The formed compound (5) canbe purified by a normal purification means such as extraction,chromatography, crystallization and suspension purification. Thereaction temperature is about −50° C to 60° C.

The process for obtaining a compound of the general formula (5) in thepreparation method of the present invention, by reacting the compound ofthe general formula (3) sequentially with a sililating agent, aphosphoric acid derivative and ammonia, can make each compound react inthe same solvent without separating it, and make it react in atemperature kept to about −20° C. to 80° C. in all steps.

The specific examples of compounds represented by the general formula(5) according to the present invention include:

(S)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone,

(R)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone,

(S)-3-tert-butyloxycarbonylamino-1-diaminophosphinyl-2-piperidone,

(R)-3-tert-butyloxycarbonylamino-1-diaminophosphinyl-2-piperidone,

(S)-3-benzoylamino-1-diaminophosphinyl-2-piperidone,

(R)-3-benzoylamino-1-diaminophosphinyl-2-piperidone,

(S)-3-acetylamino-1-diaminophosphinyl-2-piperidone,

(R)-3-acetylamino-1-diaminophosphinyl-2-piperidone,

(S)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-pyrrolidone,

(R)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-pyrrolidone,

(S)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-azetidinone,

(R)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-azetidinone,

(S)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-perhydroazepinone and

(R)-3-benzyloxycarbonylamino-1-diamino phosphinyl-2-perhydroazepinone.

A compound of the general formula (7) used in the present invention canbe prepared according to JP-A-2000-327689, or can be prepared from thecompound (5), described below, by the method according to the presentspecification.

A protecting group Y, in a compound represented by the above generalformula (7) is the same as the protecting group Y of a compoundrepresented by the general formula (1).

In the general formula (7), n is an integer of 0 to 3 and is preferably2.

Specific examples of compounds represented by the general formula (7)according to the present invention are shown in Table 1. TABLE 1Compound No. n Y C* 1 0 benzyloxycarbonyl S 2 0 benzyloxycarbonyl R 3 0p-nitrobenzyloxycarbonyl S 4 0 p-nitrobenzyloxycarbonyl R 5 0p-methoxybenzyloxycarbonyl S 6 0 p-methoxybenzyloxycarbonyl R 7 03,4-dimethoxy-6- S 0 nitrobenzyloxycarbonyl 8 0 3,4-dimethoxy-6- R 0nitrobenzyloxycarbonyl 9 0 2,4-dichlorobenzyloxycarbonyl S 10 02,4-dichlorobenzyloxycarbonyl R 11 0 p-bromobenzyloxycarbonyl S 12 0p-bromobenzyloxycarbonyl R 13 0 p-chlorobenzyloxycarbonyl S 14 0p-chlorobenzyloxycarbonyl R 15 0 9-anthrylmethyloxycarbonyl S 16 09-anthrylmethyloxycarbonyl R 17 0 tert-butoxycarbonyl S 18 0tert-butoxycarbonyl R 19 1 benzyloxycarbonyl S 20 1 benzyloxycarbonyl R21 1 p-nitrobenzyloxycarbonyl S 22 1 p-nitrobenzyloxycarbonyl R 23 1p-methoxybenzyloxycarbonyl S 24 1 p-methoxybenzyloxycarbonyl R 25 13,4-dimethoxy-6- S 1 nitrobenzyloxycarbonyl 26 1 3,4-dimethoxy-6- R 1nitrobenzyloxycarbonyl 27 1 2,4-dichlorobenzyloxycarbonyl S 28 12,4-dichlorobenzyloxycarbonyl R 29 1 p-bromobenzyloxycarbonyl S 30 1p-bromobenzyloxycarbonyl R 31 1 p-chlorobenzyloxycarbonyl S 32 1p-chlorobenzyloxycarbonyl R 33 1 9-anthrylmethyloxycarbonyl S 34 19-anthrylmethyloxycarbonyl R 35 1 tert-butoxycarbonyl S 36 1tert-butoxycarbonyl R 37 2 benzyloxycarbonyl S 38 2 benzyloxycarbonyl R39 2 p-nitrobenzyloxycarbonyl S 40 2 p-nitrobenzyloxycarbonyl R 41 2p-methoxybenzyloxycarbonyl S 42 2 p-methoxybenzyloxycarbonyl R 43 23,4-dimethoxy-6- S 2 nitrobenzyloxycarbonyl 44 2 3,4-dimethoxy-6- R 2nitrobenzyloxycarbonyl 45 2 2,4-dichlorobenzyloxycarbonyl S 46 22,4-dichlorobenzyloxycarbonyl R 47 2 p-bromobenzyloxycarbonyl S 48 2p-bromobenzyloxycarbonyl R 49 2 p-chlorobenzyloxycarbonyl S 50 2p-chlorobenzyloxycarbonyl R 51 2 9-anthrylmethyloxycarbonyl S 52 29-anthrylmethyloxycarbonyl R 53 2 tert-butoxycarbonyl S 54 2tert-butoxycarbonyl R 55 3 benzyloxycarbonyl S 56 3 benzyloxycarbonyl R57 3 p-nitrobenzyloxycarbonyl S 58 3 p-nitrobenzyloxycarbonyl R 59 3p-methoxybenzyloxycarbonyl S 60 3 p-methoxybenzyloxycarbonyl R 61 33,4-dimethoxy-6- S 3 nitrobenzyloxycarbonyl 62 3 3,4-dimethoxy-6- R 3nitrobenzyloxycarbonyl 63 3 2,4-dichlorobenzyloxycarbonyl S 64 32,4-dichlorobenzyloxycarbonyl R 65 3 p-bromobenzyloxycarbonyl S 66 3p-bromobenzyloxycarbonyl R 67 3 p-chlorobenzyloxycarbonyl S 68 3p-chlorobenzyloxycarbonyl R 69 3 9-anthrylmethyloxy carbonyl S 70 39-anthrylmethyloxycarbonyl R 71 3 tert-butoxycarbonyl S 72 3tert-butoxycarbonyl R

A method for preparing an optically active intermediate of sulphostin oranalogues thereof of the present invention, is characterized by reactinga compound represented by the general formula (7), where n is an integerof 0 to 3, Y represents a protecting group for the amino group, and aconfiguration at C* indicates either of S or R, with an optically activeamine; and resolving a formed diastereomeric salt with a fractionalcrystallization, to obtain an optically active amine salt of anoptically active compound represented by the general formula (8), wheren and Y are as described above; and each configuration at C* and P* maybe the same or different and indicates S or R.

The optically active amine in the present invention may be usually anyone commercially available which can form a crystalline salt with adiastereomer isomer of the general formula (7), but is preferably amonoacid base, which includes, for instance, derivatives of (+)- or(−)-2-amino-1-phenylethanol represented by the general formula (9),where Ar represents a phenyl group which may have a substituent group;R1′ represents a lower alkyl group which may have a substituent group oran aryl group which may have a substituent group; each of R2′ and R3′may be the same or different and represents a hydrogen atom or a loweralkyl group; and each configuration at C*1 and C*2 may be the same ordifferent and represents S or R. Each functional group and substituentgroup in the general formula (9) are as described above.

Optically active amines specifically include, for instance,(1R,2S)-(−)-2-amino-1,2-diphenylethanol,(1S,2R)-(+)-2-amino-l,2-diphenylethanol, (1R,2S)-(−)-ephedrine,(1S,2R)-(+)-ephedrine, (1R,2S)-(−)-N-methylephedrine,(1S,2R)-(+)-N-methylephedrine, (1R,2S)-(−)-4-hydroxyephedrine,(1S,2R)-(+)-4-hydroxyephedrine, (1R,2S)-(−)-norephedrine,(1S,2R)-(+)-norephedrine, (1R,2S)-(−)-3,4-dihydroxynorephedrine,(1S,2R)-(+)-3,4-dihydroxynorephedrine,(1S,2R)-(−)-2-dibutylamino-1-phenyl-1-propanol,(1R,2S)-(+)2-dibutylamino-1-phenyl-1-propanol,(1S,2S)-(+)-pseudoephedrine, (1R,2R)-(−)-pseudoephedrine,(1S,2S)-(+)-N-methylpseudoephedrine,(1R,2R)-(−)-N-methylpseudoephedrine,(1S,2S)-(+)-2-amino-3-methoxy-1-phenyl-1-propanol,(1R,2R)-(−)-2-amino-3-methoxy-1-phenyl-1-propanol,erythro-1,2-diphenyl-2-(propylamino) ethanol,erythro-2-(isopropylamino)-1,2-diphenylethanol,(1R,2R)-(−)-2-amino-1-phenyl-1,3-propanediol,(1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol,(1R,2R)-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol and(1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. Among them,preferable ones are (1R,2S)-(−)-2-amino-1,2-diphenylethanol,(1S,2R)-(+)-2-amino-1,2-diphenylethanol, (1R,2S)-(−)-ephedrine,(1S,2R)-(+)-ephedrine, (1R,2S)-(−)-N-methylephedrine,(1S,2R)-(+)-N-methylephedrine, (1R,2S)-(−)-4-hydroxyephedrine,(1S,2R)-(+)-4-hydroxyephedrine, (1R,2S)-(−)-norephedrine,(1S,2R)-(+)-norephedrine, (1R,2S)-(−)-3,4-dihydroxynorephedrine,(1S,2R)-(+)-3,4-dihydroxynorephedrine,(1S,2R)-(−)-2-dibutylamino-1-phenyl-1-propanol and(1R,2S)-(+)-2-dibutylamino-1-phenyl-1-propanol. Particularly preferableones are (1S,2R)-(+)-2-amino-1,2-diphenylethanol and(1R,2S)-(−)-2-amino-1,2-diphenylethanol.

When resolving diastereomeric salts by fractional crystallization,compounds to be resolved are usually reacted with an optically activeresolving agent to form diastereomeric salts, and only one opticallyactive substance is obtained by utilizing a difference in solubility ofthe crystal between two types of formed diastereomeric salts. Whenoptically resolving compounds which are enantiomers to one another byfractional crystallization, a resolving agent having a reverseconfiguration is used.

However, when resolving compounds which are diastereomers to one anotherrepresented by the general formula (7) used in the present invention byfractional crystallization, in contrast to optically resolving the aboveenantiomer compounds, even if using the resolving agent having thereverse configuration, the other diastereomer is not always resolved.Surprisingly, however, the present inventors found that both opticallyactive substances could be obtained by changing the molar ratio of theoptically active amine which is used as the resolving agent. This ishereafter described in detail.

As for the molar ratio of the compound of the general formula (7) to theoptically active amine which is used as the resolving agent, 0.2-1.4 molequivalent or 1.5 to 10.0 mol equivalent of the optically active aminebased on 1 mol of the compound of the general formula (7) is preferablefrom a view point of a resolution efficiency, and 0.5-1.2 mol equivalentor 1.8-5.0 mol equivalent is particularly preferable. Depending on theformer molar ratio or the latter molar ratio, isomers having differentconfigurations from each other at the phosphorus atom of the compoundrepresented by the general formula (7) can be obtained.

For instance, the reaction of a compound of the general formula (7)where a protecting group Y is a benzyloxycarbonyl group, n is 2 and theconfiguration is S at C*, with (1S,2R)-(+)-2-amino-1,2-diphenylethanolas an optionally active amine, at the former molar ratio, forms a hardlysoluble salt of a compound of the general formula (8) where a protectinggroup Y is a benzyloxycarbonyl group, n is 2 and the configuration is Sat C* and the configuration is S at P*, and(1R,2S)-(−)-2-amino-1,2-diphenylethanol, at a ratio of 1 to 1. Thus, anisomeric amine salt can be obtained at a high yield.

Use of the optically active amine is used at the latter molar ratio,forms a hardly insoluble salt of a compound of the general formula (8)where a protecting group Y is a benzyloxycarbonyl group, n is 2, and theconfiguration is S at C* and R at P*, and(1S,2R)-(+)-2-amino-1,2-diphenylethanol, at a ratio of 1 to 2. Thus, anisomeric amine salt of which the configuration on the phosphorus atom isreverse to the above one can be obtained at a high yield. This isomerhas the same absolute configuration as sulphostin, and is theintermediate which can lead to sulphostin.

When reacting (1R,2S)-(−)-2-amino-1,2-diphenylethanol which is anenantiomer reverse to the above optically active amine with a compoundof the general formula (7) where a protecting group Y is abenzyloxycarbonyl group, n is 2, and the configuration is S at C*, thereaction provides a crystalline salt regardless of the added equivalentof the amine, but the salt has little difference in solubility betweenstereoisomers and the optical resolution cannot be performed.

The reason why the reaction of a compound of the general formula (7)where a protecting group Y is a benzyloxycarbonyl group, n is 2 and theconfiguration is S at C*, with (1S,2R)-(+)-2-amino-1,2-diphenylethanolof an optically active amine forms a salt at both ratios of 1 to 1 and 1to 2, and the solubility of the formed salt is reversed, is presumed asfollows: Because the compound of the general formula (7) has a sulfonicacid, it forms a salt with one molecule of the optically active amine.When it forms a vis-a-vis (1:1) salt, sulfonic acid is stabilized by theoptically active amine; the acidity of the compound of the generalformula (7) increases; and the sulfonic acid forms a salt with one moremol equivalent of the optically active amine. It is considered that thesalt of 2 mol equivalent causes a phenomenon of reversing the solubilityby a change of a crystal structure due to the bimolecular salt. Becausethe site in the structure of the general formula (7) where the salt isformed with the amine is specified, the above phenomenon is consideredto be applicable to a salt formed of a compound where the configurationis S at C* of the general formula (7), with the optically active amine(particularly the optically active amine of the general formula (9))where the configuration is S at C*1 and R at C*2.

On the other hand, as for a compound having the configuration of R at C*in the general formula (7), when reacting 1 mol of a compound of thegeneral formula (7) with such an optically active amine of the generalformula (1) where the configuration is R at C*1 and S at C*2, in anamount of, for instance, 0.2 to 1.4 mol equivalent or 1.5 to 10.0 molequivalent, preferably 0.5 to 1.2 mol equivalent or 1.8 to 5.0 molequivalent, the reaction at the former mole ratio forms a hardly solublesalt of a compound of the general formula (8) where the configuration isR at C* and R at P*, and the optically active amine at a ratio of 1 to1, and the reaction at the latter mole ratio forms a hardly soluble saltof a compound of the general formula (8) where the configuration is R atC* and S at P*, and the optically active amine, at a ratio of 1 to 2.

Specifically, the reaction of a compound of the general formula (7)where a protecting group Y is a benzyloxycarbonyl group, n is 2 and theconfiguration is R at C*, with (1S,2R)-(−)-2-amino-1,2-diphenylethanolas a resolving agent, at the former mole ratio, forms a hardly solublesalt of a compound of the general formula (8) where a protecting group Yis the benzyloxycarbonyl group, n is 2 and the configuration is R at C*and R at P*, and (1R,2S)-(−)-2-amino-1,2-diphenylethanol, at a ratio of1 to 1; and the reaction at the latter molar ratio forms a hardlysoluble salt of the compound of the general formula (8) where aprotecting group Y is a benzyloxycarbonyl group, n is 2 and aconfiguration is R at C* and S at P*, and(1R,2S)-(−)-2-amino-1,2-diphenylethanol, at a ratio of 1 to 2. Thus,each isomeric amine salt can be obtained at a high yield.

Solvents usually used for fractional crystallization include water;alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanoland 2-butanol; ketones such as acetone, methylethylketone,methylisobutylketone, diethylketone, di-n-propylketone,diisopropylketone and methylisopropylketone; aromatic hydrocarbons suchas benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane,isopropylether, 2-methoxyethylether and diethylether; hydrocarbons suchas hexane, heptane and octane; halogenated hydrocarbons such aschloroform, dichloromethane and 1,2-dichloroethane; esters such asmethyl acetate, ethyl acetate and butyl acetate; nitryls such asacetonitril and propionitril; and a mixed solvent of suitablecombination of these solvents: and preferably include water, alcoholssuch as methanol, ethanol, 1-propanol and 2-propanol, and a mixedsolvent. The quantity to be used varies depending on the kinds of asolvent to be used, a compound of a general formula (7) and an opticallyactive amine. The rough standard is the quantity of the solvent in whichmost of a salt of a diastereomer with lower solubility is crystallied.The quantity of the solvent to be used for the fractional crystalizationis roughly about 1 to 1,000 mL for 1 g of a diastereomeric salt, and ispreferably about 2 to 200 mL.

The crystallization may be carried out by stirring the solution at atemperature of −50° C. to a boiling point of a solvent to be used,preferably at a temperature of −10° C. to −110° C., and for 1 minute to120 hours, to accumulate a diastereomeric salt having a lower solubilityin the solvent out of the two kinds of diastereomeric salts, thencooling the solution to a temperature of −30° C. to 40° C., andseparating a precipitated diastereomeric salt.

Thus obtained diastereomeric salt, after a protecting group Y for anamino group and an optically active amine are removed therefrom, can beled to sulphostin or analogues thereof represented by the generalformula (1). This preparation method is also included by the presentinvention. As for removing the protecting group, a method suitable foreach protecting group may be employed, and a well-known method isemployed. For instance, a benzyloxycarbonyl group can be removed byhydrogenation decomposition through catalytic reduction, atert-butoxycarbonyl group by acid treatment, ap-methoxybenzyloxycarbonyl group by hydrogenation decomposition throughcatalytic reduction or by acid treatment.

The compound represented by the general formula (1) produced by theabove method, has the same behaviour in chromatography, physico-chemicalproperties, an inhibitory effect against dipeptidyl peptidase IV asthose of sulphostin and sulphostin analogues according toJP-A-2000-327689.

In addition, the steps of; dissolving a compound represented by thegeneral formula (5′) (wherein n denotes an integer of 0 to 3; Yrepresents a protecting group for an amino group; and a configuration atC* and P* may be each the same or different and indicates S or R)provided by the method of JP-A-2000-327689, in a solvent such as DMF;sulfonating it with sulfur trioxide, specifically sulfur trioxide, asulfur trioxide-pyridine complex, a sulfur trioxide-trimethyl aminecomplex or a sulfur trioxide-N,N-dimethylformamide complex; then withoutisolating the formed compound of the general formula (7), resolving itby fractional crystallization using the optically active amine describedabove; and further deprotecting the amino group, can provide opticallyactive sulphostin or the analogues thereof. This preparation method isalso included by the present invention.

Furthermore, by combining the preparation steps described above, thesulphostin and the sulphostin analogues represented by the generalformula (4) can be prepared from the compound of the general formula(1). Such a serial preparation method is also included by the presentpatent.

The present invention includes a salt of an optically active compoundrepresented by the general formula (8) (wherein n denotes an integer of0 to 3; Y represents a protecting group for an amino group; and aconfiguration at C* and P* may be each the same or different andindicates S or R ) and an optically active amine represented by thegeneral formula (9) (wherein Ar donotes a phenyl group which may have asubstituent group; R1′ indicates a lower alkyl group which may have asubstituent group or an aryl which may have a substituent group; R2′ andR3′ may be each the same or different and indicates a hydrogen atom or alower alkyl group; and a configuration at C*1 and C*2 may be each thesame or different and indicates S or R). The protecting group Y for theamino group in the general formula (8) includes the same groups as theprotecting group Y for the amino group in the above general formula (7).The preferred groups are also described above. The n in the generalformula (8) is the same as in the general formula (7), and is preferably2. The optically active amine which is represented by the generalformula (9) includes the amine compound described in the abovepreparation method, and the preferred compound is also described above.Naturally, an monoamine salt and a diamine salt are also included in thepresent invention.

The amines specifically include, for instance,(1S,2R)-(+)-2-amino-1,2-diphenylethanol salts of(3S)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-p-nitrobenzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-p-methoxybenzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-(3,4-dimethoxy-6-nitrobenzyloxycarbonyl)amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-(2,4-dichlorobenzyloxycarbonyl)amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-p-bromobenzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-p-chlorobenzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-(9-anthrylmethyloxycarbonyl)amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidoneand(3S)-3-tert-butoxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone;2{(1S,2R)-(+)-2-amino-1,2-diphenylethanol} salts of(3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-p-nitrobenzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-p-methoxybenzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-(3,4-dimethoxy-6-nitrobenzyloxycarbonyl)amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-(2,4-dichlorobenzyloxycarbonyl)amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-parabromobenzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-p-chlorobenzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3S)-3-(9-anthrylmethyloxycarbonyl)amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidoneand(3S)-3-tert-butoxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone;(1R,2S)-(−)-2-amino-1,2-diphenylethanol salts of(3R)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-p-nitrobenzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-p-methoxybenzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-(3,4-dimethoxy-6-nitrobenzyloxycarbonyl)amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-(2,4-dichlorobenzyloxycarbonyl)amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-p-bromobenzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-p-chlorobenzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-(9-anthrylmethyloxycarbonyl)amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidoneand(3R)-3-tert-butoxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone;and 2{(1R, 2S)-(−)-2-amino-1,2-diphenylethanol} salts of(3R)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-p-nitrobenzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-p-methoxybenzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-(3,4-dimethoxy-6-nitrobenzyloxycarbonyl)amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-(2,4-dichlorobenzyloxycarbonyl)amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-p-bromobenzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-p-chlorobenzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone,(3R)-3-(9-anthrylmethyloxycarbonyl)amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidoneand(3R)-3-tert-butoxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone.

The present invention is specifically explained below with reference tothe following examples, but is not limited to them. Room temperaturehereafter means 10° C. to 30° C. NMR value in the examples is δ (ppm)measured by using tetramethylsilane (TMS) or sodium salt of3-(trimethylsilyl) propionic-2,2,3,3-d₄-acid (TSP) as an internalstandard.

The optical purity (d.e.) of a phosphorus atom was measured in thefollowing method.

20 mg (1.0 eq.) of a resulting compound and 33 mg (5.0 eq.) of sodiumbicarbonate were dissolved into 10 mL of water, and 5 mL oftetrahydrofuran (THF) was added thereto. Then, 25 μL (2.5 eq.) ofbenzyloxycarbonyl chloride was added thereto, the solution was stirredfor 30 minutes so that the amino group was benzyloxycarbonylated. Thereaction mixture was analyzed with a high-speed liquid chromatographyusing an ODS column (PEGASIL ODS made by SSC Sensyu science Co., Ltd.).

EXAMPLE 1 (S)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone

600 g (2.42 mol) of (S)-3-benzyloxycarbonylamino-2-piperidone was addedto 6 L of toluene and 823 mL (4.80 mol) of diisopropylethylamine,subsequently 612 mL (4.80 mol) of trimethylsilyl chloride was addeddropwise, and the solution was stirred at room temperature for 24 hours.Subsequently, 894 mL (9.60 mol) of phosphorus oxychloride was addeddropwise, and the solution was stirred at room temperature for 48 hours.An ammonia water adjusted to a pH of about 10 with ammonium chloride wascooled to −10° C. or lower, and the reacted solution was added dropwiseinto it. When the pH falls to less than 9, the ammonia water was added.The obtained suspension was filtered, and the residue was washed with 3L of toluene, subsequently 2 L of a toluene-THF mixed solvent, and thenextracted with 10 L of a THF-methanol mixed solvent. The extractedliquid was vacuum-concentrated, the residue was washed with 6 L of waterand suspension-purified with 10 L of an ethanol-diisopropylether mixedsolvent, and 345.7 g of (S)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (1.06 mol and a yield of 43.8%) was obtained.

¹H-NMR (200 MHzFT, TMS, DMSO-D6) 1.58-1.66 (1H, m), 1.73-1.78 (2H, m),1.98-2.03 (1H, m), 3.43-3.48 (1H, m), 3.55-3.61 (1H, m), 4.06-4.12 (1H,m), 4.14 (2H, brs), 4.19 (2H, brs), 5.00 (2H, s), 7.28-7.41 (6H, m).

The compound was analyzed with high-speed liquid chromatography by usingan optically active column (CHIRALPACK AS made by Daicel ChemicalIndustries, Ltd.) to prove to have an optical purity (ee) of higher than99%.

EXAMPLE 2 Preparation of a Salt of(3S)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidonewith (1S,2R)-(+)-2-amino-1,2-diphenylethanol

50 mL of water and 2.45 mL of 1 N hydrochloric acid was added to 1.05 g(2.35 mmol) of a mixture of a sodium salt of(3S)-3-benzyloxycarbonylamino-(S)-1-amino (sulfoamino)phosphinyl-2-piperidone and a sodium salt of(3S)-3-benzyloxycarbonylamino-(R)-1-amino (sulfoamino)phosphinyl-2-piperidone at about 1:1, which are obtained according toJP-A-2000-327689, and 522 mg (2.45 mmol) of (1S, 2R)-(+)-2-amino-1,2-diphenylethanol; and the reaction liquid was stirred while beingheated. Both compounds were completely dissolved at an inner temperatureof about 50° C., heating was stopped, and the reaction liquid was lefttill the inner temperature becomes room temperature. The precipitatedcrystal was taken through filtration, and 656 mg of a salt of(3S)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidonewith (1S, 2R)-(+)-2-amino-1,2-diphenylethanol (1.06 mmol, an opticalpurity (d.e.) of 90%, and a yield of 45%) was obtained. As a result ofmeasuring the optical purity (d.e.) of the filtrate, it proved tocontain(3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)-phosphinyl-2-piperidoneof 90% (d.e.).

salt of (3S)-3-benzyloxycarbonylamino-(S)-1-amino (sulfo amino)phosphinyl-2-piperidone with (1S, 2R)-(+)-2-amino-1,2-diphenylethanol

¹H-NMR (200 MHzFT, TMS, CD₃OD) 1.65-2.00 (3H, m), 2.12-2.20 (1H, m),3.50-3.88 (2H, m), 4.16-4.30 (1H, m), 4.46 (1H, d, J=4.1 Hz), 5.08 (2H,s), 5.22 (1H, d, J=4.1 Hz), 7.04-7.42 (15H, m)

EXAMPLE 3 Preparation of(3S)-3-amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone

3.68 g of Palladium black was added to a suspending solution containing73.56 g (119 mmol) of the salt of(3S)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidonewith (1S, 2R)-(+)-2-amino-1,2-diphenylethanol in 150 mL of acetic acidand 375 mL of water, and the solution was stirred in a hydrogen flow atroom temperature for 24 hours. The catalyst was removed by filtration(with the use of 500 mL of water for washing) from the reacted solution,and 2.0 L of ethanol was added dropwise to the obtained filtrate. Theprecipitated crystal was taken through filtration, and 24.5 g of(3S)-3-amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone (84.4 mmol,an optical purity (d.e.) of 98.5%, and a yield of 71%) was obtained.

(3S)-3-amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone

¹H-NMR (400 MHzFT, TSP, D₂O) 1.85-2.12 (3H, m), 2.37-2.45 (1H, m),3.63-3.74 (2H, m), 4.13 (1H, dd, J=6.5, 7.0 Hz) ¹³C-NMR (100 MHzFT, TSP,D₂O) 23.1, 26.7, 47.8, 53.4, 174.5 MS (FAB, POS) m/Z: 273 [M+H]⁺ [α]D²⁰=+43.8° (water, c=0.5)

EXAMPLE 4 Preparation of the salt of(3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidonewith 2{(1S,2R)-(+)-2-amino-1,2-diphenylethanol}

350 mL of ethanol, 200 mL of water and 16.2 mL of 1 N hydrochloric acidwere added to 6.94 g (16.2 mmol) of a mixture containing a sodium saltof(3S)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidoneand a sodium salt of(3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidoneat about 1:1, and 7.96 g (37.3 mmol) of (1S,2R)-(+)-2-amino-1,2-diphenylethanol, and the reaction liquid was stirredwhile being heating. Both compounds were completely dissolved at aninner temperature of about 55° C., heating was stopped, and the reactionliquid was left till the inner temperature becomes room temperature. Theprecipitated crystal was taken through filtration, and 5.4 g of a saltof (3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone with 2{(1S,2R)-(+)-2-amino-1,2-diphenylethanol}(6.48 mmol, an optical purity (d.e.) of 95%, and a yield of 40%) wasobtained. As a result of measuring the optical purity (d.e.) of thefiltrate, it proved to contain(3S)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidoneof 80% (d.e.).

salt of(3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidonewith 2{(1S, 2R)-(+)-2-amino-1,2-diphenylethanol}

1H-NMR (200 MHzFT, TMS, CD₃OD) 1.65-1.90 (2H, m), 1.95-2.25 (2H, m),3.50-3.68 (1H, m), 3.75-3.94 (1H, m), 4.20-4.34 (3H, m), 5.04 (2H, d,J=4.9 Hz), 5.09 (2H, s), 7.10-7.40 (25H, m)

EXAMPLE 5 Preparation of(3S)-3-amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone (sulphostin)

50 mg of palladium black was added to a suspension containing 1.0 g(1.20 mmol) of the salt of(3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidonewith 2{(1S,2R)-(+)-2-amino-1,2-diphenylethanol} in 2 mL of acetic acidand 5 mL of water, and the solution was stirred in a hydrogen flow atroom temperature for 2 hours. The catalyst was removed by filtration(with the use of water of 6 mL for washing) from the reacted solution,and 21 mL of ethanol was added dropwise to the obtained filtrate. Theprecipitated crystal was taken through filtration, and 281 mg of(3S)-3-amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone (0.968 mmol,an optical purity (d.e.) of 98.6%, and a yield of 81%) was obtained.Then, the product was recrystalized with the use of a water-ethanolsolvent, and the desired(3S)-3-amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone (sulphostin)(a chemical purity of more than 99%, and an optical purity (d.e.) ofmore than 99%) was obtained.

(3S)-3-amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone (sulphostin)

¹H-NMR (400MHzFT, TSP, D₂O) 1.85-2.02 (2H, m), 2.06-2.17 (1H, m),2.35-2.45 (1H, m), 3.61-3.69 (1H, m), 3.74-3.83 (1H, m), 4.15 (1H, dd,J=6.9,11.9 Hz) ¹³C-NMR (100 MHzFT, TSP, D₂O) 22.6, 26.3, 47.5, 53.4,174.5 MS (ESI, NEG) m/Z: 271 [M−H]⁻[α] D²⁰=−21.8° (water, c=5.03)

EXAMPLE 6 Preparation of the Salt of(3R)-3-benzyloxycarbonylamino-(R)-1-amino (sulfoamino)phosphinyl-2-piperidone with (1R,2S)-(−)-2-amino-1,2-diphenylethanol

5.0 mL of water and 0.21 mL of 1 N hydrochloric acid was added to 90 mg(0.21 mmol) of a mixture of a sodium salt of(3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidoneand a sodium salt of(3R)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidoneat about 1:1, and 42.6 mg (0.20 mmol) of (1R,2S)-(−)-2-amino-1,2-diphenylethanol; and the reaction liquid was stirredwhile being heated. Both compounds were completely dissolved at an innertemperature of about 50° C., heating was stopped, and the reactionliquid was left till the inner temperature becomes room temperature. Theprecipitated crystal was taken through a filter, and 25 mg of a salt of(3R)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone with (1R,2S)-(−)-2-amino-1,2-diphenylethanol(0.040 mmol, an optical purity (d.e.) of 95%, and a yield of 19%) wasobtained.

salt of(3R)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidonewith (1R,2S)-(−)-2-amino-1,2-diphenylethanol

¹H-NMR (200 MHzFT, TMS, CD₃OD) 1.63-2.02 (3H, m), 2.12-2.30 (1H, m),3.50-3.88 (2H, m), 4.17-4.30 (1H, m), 4.46 (1H, d, J=4.0 Hz), 5.08 (2H,s), 5.22 (1H, d, J=4.0 Hz), 7.04-7.41 (15H, m)

EXAMPLE 7 Preparation of(3R)-3-amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone

90 mg of Palladium black was added to a suspension containing 1.35 g(2.18 mmol) of the salt of(3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidonewith (1R, 2S)-(−)-2-amino-1,2-diphenylethanol of in 3 mL of acetic acidand 15 mL of water, and the solution was stirred in a hydrogen flow atroom temperature for 24 hours. The catalyst was removed by filtration(with the use of 15 mL of water for washing) from the reacted solution,and 80 mL of ethanol was added dropwise to the obtained filtrate. Theprecipitated crystal was taken through a filter, and 304 mg of(3R)-3-amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone (1.05 mmol,an optical purity (d.e.) of 95.4%, and a yield of 48%) was obtained.

(3R)-3-amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone

¹H-NMR (200 MHzFT, TSP, D₂O) 1.79-2.12 (3H, m), 2.33-2.48 (1H, m),3.65-3.74 (2H, m), 4.15 (1H, dd, J=7.4,11.4 Hz) MS (FAB, POS) m/Z:273[M+H]⁺ [α]_(D) ²⁰=−43.6° (water, c=0.5)

EXAMPLE 8 Preparation of the Salt of(3R)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidonewith 2{(1R,2S)-(−)-2-amino-1,2-diphenylethanol}

125 mL of ethanol, 95 mL of water and 5.6 mL of 1 N hydrochloric acidwere added to 2.4 g (5.60 mmol) of a mixture of the sodium salt of(3R)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidoneand the sodium salt of(3R)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidoneat about 1:1, and 2.63 mg (12.3 mmol) of(1R,2S)-(−)-2-amino-1,2-diphenylethanol; and the reaction liquid wasstirred while being heated. Both compounds were completely dissolved atan inner temperature of about 50° C., heating was stopped, and thereaction liquid was left till the inner temperature becomes roomtemperature. The precipitated crystal was taken through a filter, and1.95 g of a salt of(3R)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone with 2{(1R,2S)-(−)-2-amino-1,2-diphenylethanol}(2.34 mmol, an optical purity (d.e.) of 95.6%, and a yield of 42%) wasobtained. As a result of measuring the optical purity (d.e.) of thefiltrate, the filtrate proved to contain(3R)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidoneof 83.4% (d.e.).

salt of(3R)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidonewith 2{(1R,2S)-(−)-2-amino-1,2-diphenylethanol}

¹H-NMR (200 MHzFT, TMS, CD₃OD) 1.55-1.77 (2H, m), 1.85-2.05 (2H, m),3.00-3.80 (2H, m), 4.18-4.30 (3H, m), 4.86 (2H, d, J=4.8 Hz), 5.08 (2H,s), 7.07-7.43 (25H, m)

EXAMPLE 9 Preparation of(3R)-3-amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone

140 mg of palladium black was added to a suspension containing 2.7 g(3.24 mmol) of the salt of(3R)-3-benzyloxycarbonylamino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidonewith 2{(1R,2S)-(−)-2-amino-1,2-diphenylethanol} in 5 mL of acetic acidand 25 mL of water, and the solution was stirred in a hydrogen flow atroom temperature for 24 hours. The catalyst was removed by filtration(with the use of 15 mL of water for washing) from the reacted solution,and 80 mL of ethanol was added dropwise to the obtained filtrate. Theprecipitated crystal was taken through a filter, and 711 mg of(3R)-3-amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone (2.45 mmol,an optical purity (d.e.) of 98.8%, and a yield of 76%) was obtained.

(3R)-3-amino-(S)-1-amino(sulfoamino)phosphinyl-2-piperidone

¹H-NMR (200 MHzFT, TSP, D₂O) 1.79-2.24 (3H, m), 2.30-2.47 (1H, m),3.56-3.90 (2H, m), 4.15 (1H, dd, J=7.3,11.2 Hz) MS (FAB, POS) m/Z: 273[M+H]⁺ [α]_(D) ²⁰=+21.5° (water, c=0.5)

EXAMPLE 10 Preparation of(3S)-3-amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone (sulphostin)

294 g (0.901 mol) of(S)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone describedin JP-A-2000-327689 was dissolved in 3.0 L of DMF heated to 60° C., thenthe reaction liquid was cooled to 10° C. or lower, 172 g (1.08 mol) ofthe sulfur trioxide-pyridine complex was added to it, and the reactionliquid was stirred for one hour. To the reaction liquid, 100 mL ofwater, then 1.0 L of methanol and a half of 4.0 L of a solution inmethanol containing 480 g (2.25 mol) of (1S,2R)-(+)-2-amino-1,2-diphenylethanol, which had been prepared beforehand,were added, and the reaction liquid was heated to 50° C. at the innertemperature. The remaining methanol solution of(1S,2R)-(+)-2-amino-1,2-diphenylethanol was all added, the solution wasstirred for 30 minutes, then the precipitated crystal was removedthrough a filter, and methanol in the filtrate was vacuum concentrated.15.0 L of ethanol and 6.0 L of water were added to the obtained residue,the liquid was stirred for 16 hours, and the precipitated crystal wastaken through a filter so that 257 g of the salt of(3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidonewith 2{(1S,2R)-(+)-2-amino-1,2-diphenylethanol} (an optical purity of92% d.e.) was obtained.

11 g of palladium black was added to a suspension containing 257 g ofthe resultant salt of(3S)-3-benzyloxycarbonylamino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidonewith 2{(1S,2R)-(+)-2-amino-1,2-diphenylethanol} in 400 mL of acetic acidand 2.0 L of water, and the solution was stirred in a hydrogen flow atroom temperature for 3 hours. The catalyst was removed by filtration(with the use of water of 500 mL for washing) from the reacted solution,and 5.0 L of ethanol was added dropwise to the resultant filtrate. Theprecipitated crystal was taken through a filter, and 59.5 g of(3S)-3-amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone (0.205 mol,an optical purity (d.e.) of 97.6%, and a yield from(S)-3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone of 23%)was obtained. Then, the product was recrystalized with the use of awater-ethanol solution, and the desired(3S)-3-amino-(R)-1-amino(sulfoamino)phosphinyl-2-piperidone (sulphostin)(a chemical purity of more than 99%, and an optical purity (d.e.) ofmore than 99%) was obtained.

INDUSTRIAL APPLICABILITY

The present invention enables the preparation of optically activesulphostin and analogues of sulphostin having dipeptidylpeptidase IVinhibitory activity represented by the general formula (1), andcompounds as preparation intermediates thereof represented by thegeneral formula (5) or (8), in an easier way and a larger quantity ascompared to the conventional techniques and at a superior purity andyield.

1. A method for preparing a compound represented by the followinggeneral formula (5)

where, n is an integer of 0 to 3; and Y represents a protecting groupfor an amino group, comprising the steps of reacting a compoundrepresented by the following general formula (3)

where, n and Y are as described above, with a sililating agent,subsequently reacting it with a phosphorus oxyhalide represented by thegeneral formula (4)P(═O)t₃  (4) where t represents a halogen atom and further with ammonia.2. The preparing method according to claim 1, wherein the Y is aprotecting group of a carbamate type or an amide type.
 3. Thepreparation method according to claim 2, wherein the Y is abenzyloxycarbonyl group or a tert-butoxycarbonyl group optionallysubstituted, and n is
 2. 4. The preparation method according to any oneof claims 1 to 3, wherein the compound represented by the generalformula (3) is an optically active substance.
 5. The preparation methodaccording to any one of claims 1 to 4, wherein T is a chlorine atom inthe general formula (4).
 6. The preparation method according to any oneof claims 1 to 5, wherein the silylating agent is represented by thefollowing general formula (6)

where R1, R2 and R3 each independently represent a lower alkyl group oran aryl group; and X represents a halogen atom or a fluorinated alkylsulfonate.
 7. The preparation method according to claim 6, wherein thesilylating agent is trimethylsilyl chloride.
 8. The preparation methodaccording to any one of claims 1 to 7, wherein a reaction temperature is−20° C. to 80° C. in the steps of preparing a compound represented bythe general formula (5) from a compound represented by the generalformula (3).
 9. A method for preparing an optically active intermediateof optically active sulphostin or an analogue thereof, which is anoptically active amine salt of the optically active compound representedby the following general formula (8)

where n is an integer of 0 to 3; Y represents a protecting group for theamino group; and each configuration at C* and P* may be the same ordifferent and indicates S or R, comprising the steps of resolving thediastereomeric salt formed by reacting a compound represented by thefollowing general formula (7)

where n and Y are as described above; and the configuration of C*indicates either of S or R, with an optically active amine, andresolving a formed diastereomeric salt by fractional crystallization.10. A method for preparing an optically active sulphostin or an analoguethereof represented by the following general formula (1)

where n is an integer of 0 to 3; and each configuration of C* and P* maybe the same or different and indicates S or R, comprising the steps ofreacting a compound represented by the following general formula (7)

where n is an integer of 1 to 3, Y represents a protecting group for anamino group; and a configuration of C* indicates either of S or R, withan optically active amine, resolving a formed diastereomeric salt byfractional crystallization to obtain an optically active amine salt ofan optically active compound represented by the following generalformula (8)

where n is an integer of 1 to 3, Y represents the protecting group forthe amino group; C* and P* have the same meanings as above), and thenremoving the protecting group for the amino group and the opticallyactive amine by a conventional process.
 11. The method according toclaim 9 or 10, wherein the optically active amine is represented by thefollowing general formula (9)

where Ar represents a phenyl group which may have a substituent group;R1′ represents a lower alkyl group which may have a substituent group,or an aryl group which may have a substituent group; each of R2′ and R3′may be the same or different and represents a hydrogen atom or a loweralkyl group; each configuration of C*1 and C*2 may be the same ordifferent and indicates S or R.
 12. The method according to claim 9 or10, wherein the above optically active amine is a compound selected fromthe group consisting of (1R,2S)-(−)-2-amino-1,2-diphenylethanol,(1S,2R)-(+)-2-amino-1,2-diphenylethanol, (1R,2S)-(−)-ephedrine,(1S,2R)-(+)-ephedrine, (1R,2S)-(−)-N-methylephedrine,(1S,2R)-(+)-N-methylephedrine, (1R,2S)-(−)-4-hydroxyephedrine,(1S,2R)-(+)-4-hydroxyephedrine, (1R,2S)-(−)-norephedrine,(1S,2R)-(+)-norephedrine, (1R,2S)-(−)-3,4-dihydroxynorephedrine,(1S,2R)-(+)-3,4-dihydroxynorephedrine,(1S,2R)-(−)-2-dibutylamino-1-phenyl-1-propanol,(1R,2S)-(+)-2-dibutylamino-1-phenyl-1-propanol,(1S,2S)-(+)-pseudoephedrine, (1R,2R)-(−)-pseudoephedrine,(1S,2S)-(+)-N-methyl pseudoephedrine, (1R,2R)-(−)-N-methylpseudoephedrine, (1S,2S)-(+)-2-amino-3-methoxy-1-phenyl-1-propanol,(1R,2R)-(−)-2-amino-3-methoxy-1-phenyl-1-propanol,erythro-1,2-diphenyl-2-(propylamino)ethanol,erythro-2-(isopropylamino)-1,2-diphenylethanol,(1R,2R)-(−)-2-amino-1-phenyl-1,3-propanediol,(1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol,(1R,2R)-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol and(1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.
 13. The methodaccording to claim 9 or 10, wherein the optically active amine is acompound selected from the group consisting of(1R,2S)-(−)-2-amino-1,2-diphenylethanol,(1S,2R)-(+)-2-amino-1,2-diphenylethanol, (1R,2S)-(−)-ephedrine,(1S,2R)-(+)-ephedrine, (1R,2S)-(−)-N-methylephedrine,(1S,2R)-(+)-N-methylephedrine, (1R,2S)-(−)-4-hydroxyephedrine,(1S,2R)-(+)-4-hydroxyephedrine, (1R,2S)-(−)-norephedrine,(1S,2R)-(+)-norephedrine, (1R,2S)-(−)-3,4-dihydroxynorephedrine,(1S,2R)-(+)-3,4-dihydroxynorephedrine,(1S,2R)-(−)-2-dibutylamino-1-phenyl-1-propanol and(1R,2S)-(+)-2-dibutylamino-1-phenyl-1-propanol.
 14. The method accordingto claim 9 or 10, wherein the optically active amine is(1R,2S)-(−)-2-amino-1,2-diphenylethanol or(1S,2R)-(+)-2-amino-1,2-diphenylethanol.
 15. The method according to anyone of claims 9 to 14, wherein the Y in the general formula (7) is aprotecting group of a carbamate type or an amide type.
 16. The methodaccording to any one of claims 9 to 14, wherein the Y in the generalformula (7) is a benzyloxycarbonyl group or a tert-butoxycarbonyl groupthat may have a substituent group; and n is
 2. 17. The method accordingto any one of claims 9 to 14, wherein the Y in the general formula (7)is an unsubstituted benzyloxycarbonyl group; and n is
 2. 18. The methodaccording to any one of claims 9 to 17, wherein the compound having theconfiguration of S at C* and the configuration of S at P* in the generalformula (8) is obtained by reacting 1 mol of a compound having theconfiguration of S at C* in the above general formula (7), with 0.2 to1.4 mol equivalent of the optically active amine having theconfiguration of S at C*1 and the configuration of R at C*2 in thegeneral formula (9), as a hardly soluble salt consisting of 1 part ofitself and 1 part of the optically active amine.
 19. The methodaccording to any one of claims 9 to 17, wherein the compound having theconfiguration of S at C* and the configuration of R at P* in the generalformula (8) is obtained by reacting 1 mol of a compound having theconfiguration of S at C* in the general formula (7), with 1.5 to 10.0mol equivalent of the optically active amine having the configuration ofS at C*1 and the configuration of R at C*2 in the general formula (9),as a hardly soluble salt consisting of 1 part of itself and 2 part ofthe optically active amine.
 20. The method according to any one ofclaims 9 to 17, wherein the compound having the configuration of R at C*and the configuration of R at P* in the general formula (8) is obtainedby reacting 1 mol of a compound having the configuration of R at C* inthe above general formula (7), with 0.2 to 1.4 mol equivalent of theoptically active amine having the configuration of R at C*1 and theconfiguration of S at C*2 in the general formula (9), as a hardlysoluble salt consisting of 1 part of itself and 1 part of the opticallyactive amine.
 21. The method according to any one of claims 9 to 17,wherein the compound having the configuration of R at C* and theconfiguration of S at P* in the general formula (8) is obtained byreacting 1 mol of a compound having the configuration of R at C* in thegeneral formula (7), with 1.5 to 10.0 mol equivalent of the opticallyactive amine having the configuration of R at C*1 and the configurationof S at C*2 in the general formula (9), as a hardly soluble saltconsisting of 1 part of itself and 2 part of the optically active amine.22. The method according to claim 9, wherein the optically active aminesalt of an optically active substance represented by the followinggeneral formula (8)

where n is an integer of 0 to 3; Y represents a protecting group for theamino group; and each configuration at C* and P* may be same ordifferent and indicates S or R, is obtained by sulfonating a compoundrepresented by the following general formula (5′)

where n and Y are as described above; and the configuration at C*indicates S or R, by sulfur trioxide, reacting the resulting compoundrepresented by the general formula (7) with an optically active aminewithout isolating it, and resolving the formed diastereomeric salt witha fractional crystalliation process.
 23. The preparation methodaccording to any one of claims 1, 9, 10 and 22, wherein optically activesulphostin or analogue thereof represented by the following generalformula (1)

where n is an integer of 0 to 3; each configuration at C* and P* may bethe same or different and indicates S or R, is obtained by reacting acompound represented by the following general formula (3′)

where n is an integer of 1 to 3, Y represents a protecting group for theamino group; and the configuration at C* indicates S or R, sequentiallywith a sililating agent, with a phosphorus oxyhalide represented by thegeneral formula (4)P(═O)T₃  (4) where T represents a halogen atom, and further withammonia; sulfonating the resulting compound represented by the followinggeneral formula (5′)

where n, Y and C* are as described above), with sulfur trioxide;reacting the resulting compound represented by the general formula (7)with an optically active amine, without isolating it; resolving theformed diastereomeric salt with a fractional crystallization process toobtain an optically active amine salt of the optically active substancerepresented by the following general formula (8)

where n and Y are as described above; and C* and P* have the samemeanings as above); and then removing the protecting group for the aminogroup and the optically active amine with a conventional process.
 24. Asalt of an optically active compound represented by the followinggeneral formula (8)

where n is an integer of 0 to 3; Y represents a protecting group for theamino group; and each configuration at C* and P* may be the same ordifferent and indicates S or R, with an optically active aminerepresented by the following general formula (9)

where Ar represents a phenyl group which may have a substituent group;R1′ represents a lower alkyl group which may have a substituent group,or an aryl group which may have a substituent group; each of R2′ and R3′may be the same or different and represents a hydrogen atom or a loweralkyl group; and each configuration at C*1 and C*2 may be the same ordifferent and indicates S or R.
 25. The salt according to claim 24,wherein the above optically active amine is(1R,2S)-(−)-2-amino-1,2-diphenylethanol or(1S,2R)-(+)-2-amino-1,2-diphenylethanol.